Epidemiological studies in humans have shown a marked decrease in colon and other cancers that correlates with the use of nonsteroidal antiinflammatory drugs (NSAIDs). We have demonstrated that COX-1 and COX-2 deficiencies reduce skin tumorigenesis and believe this reduction is due to altered differentiation. By IHC of keratins in the epidermis of DMBA/TPA treated mice, we have demonstrated differences in keratinocyte differentiation between the wild type and COX null mice. The basal keratinocytes of COX deficient mice began terminal differentiation prematurely, as K1 and K10 are expressed in a high percentage of these cell in the COX deficient mice compared to wild type mice. This premature onset of terminal differentiation would continually remove initiated cell from the replicative population and decrease tumor growth and numbers. Surprisingly, apoptosis of keratinocytes of the COX deficient mice was not significantly increased compared to the level observed in wild type mice. Thus, the data suggest that altered terminal differentiation of keratinocytes may be a COX dependent mechanism by which NSAIDs reduce skin tumorigenesis.